Process for modifying drug crystal formation

ABSTRACT

A process for modifying the crystal habit of acicular drug substances, crystals obtained by such a process, and particular crystal forms or modifications of mycophenolic acid or mycophenolate sodium are provided, as well as pharmaceutical compositions comprising the crystals, methods of treatment and uses thereof.

The present invention relates to a process for modifying the crystalhabit of acicular drug substances, to the resulting crystallized drugsubstances and to pharmaceutical compositions comprising the same.

Industrial crystallization inter alia aims at producing crystals of adefined quality such as shape, particle size and/or bulk density.

Usually, crystals grow in three directions, length, width and height.Some crystals however, have one or two preferred growth directions. Forexample, acicular substances e.g. crystals in the form of needles, rodsor capillaries, have a preferred crystal growth in one direction. Theratio between the length and the width of a crystal, the so-calledaspect ratio, is significantly higher than 1:1 for acicular crystals;the higher the aspect ratio, the longer the crystal needles, rods orcapillaries.

Acicular crystals often display poor processability, inefficientprocessing, e.g. for the manufacture of galenical formulations, tend tohave a poor flowability and/or a low bulk density, e.g. a bulk densityof below about 200 kg/m³. Thus the formulation of e.g. tabletscomprising said crystalline material may result in e.g. low mechanicalstability of the formulation, an undesirably large dosage form and/ormay require special compression methods.

It is thus desirable to modify the crystal habit, i.e. the relativerates of the growth of the crystal In different directions, of acicularcrystals. This may be achieved by retarding the crystal growth of thepreferred growth direction, and/or enhancing the growth of the lesspreferred growth directions. Preferably, such a process does not have aneffect on polymorphism.

Retardation of a crystal growth direction may be achieved e.g. byadditives that act as competitive agents and adsorb onto the fastestgrowing face and thus hinder crystal growth in this direction. Inice-cream technology this method is very well established. Carrageenanis added to inhibit needlelike growth of water crystals in order toavoid an “icy” taste. Another example is the addition of additives todiesel fuel in winter that prevents paraffin crystals from growing inlong needles that would clog the fuel lines. In case of a drugsubstance, the addition of an additive Is however problematic.

Solvents have been used to influence the crystal habit of the solute,however, with an unsatisfactory effect.

Increase of particle size of acicular crystals has been achieved bytemperature oscillation. When using temperature oscillation, crystalsmay however grow bigger without changing or without changingsubstantially the crystal habit.

Temperature oscillation has been combined with sonication to modify thecrystal habit of crystalline needles. The sonication limits the growthof the length of the needles by breaking them. Therefore, this processIs not convenient for industrial crystallization as it may cause e.g.severe noise and abrasion of equipment.

Thus, there is a need for a crystallization process for acicular drugsubstances leading to improved crystal growth, particularly applicableto industrial manufacture.

Applicants have now found a process for modifying the crystal habit ofacicular crystals of a drug substance yielding a crystalline drugsubstance with improved bulk density and/or a reduced mean aspect ratio.Additional steps, such as sonication or application shear forces withhigh-shear mixers or homogenizers, for breaking the crystals, are notrequired.

The drug substance obtained in accordance with the process of theinvention preferably has a bulk density above about 200 kg/m³, e.g.about 300 to about 600 kg/m³, and/or the mean aspect ratio is smallerthan about 10:1, e.g. between about 1:1 and about 10:1, e.g. about 5:1,e.g. about 2:1.

Accordingly, the present invention provides a process for modifying thecrystal habit of acicular drug substances comprising suspending saidcrystals in a solvent system having an effect on the crystal habit andsubjecting said suspension to a temperature oscillation. In anotherembodiment, the present invention provides a process forrecrystallization of acicular drug substances comprising suspending saidcrystals in a solvent system having an effect on the crystal habit andsubjecting said suspension to a temperature oscillation. The presentinvention further provides a process for producing crystals of anacicular drug substance having a bulk density of above about 200 kg/m³,preferably about 300 to about 600 kg/m³, and/or a mean aspect ratio ofbelow about 10:1, more preferably below about 5:1, even more preferablybelow about 2:1. The particle size of the crystals may be increased bysaid process.

The solvent system having an effect on the crystal habit retards thecrystal growth of the preferred growth direction and/or enhances thecrystal growth of the less preferred crystal faces. The effect of thesolvent system on the crystal habit may be small and may be enhanced bytemperature oscillation.

By “solvent system” is meant a solvent or solvent mixture comprisingoptionally an additive. The solvent system may be removed at the end ofthe crystallization process, e.g. evaporated when drying the processedcrystals, preferably it is removed.

Typically, the solvent system is chosen in a way that chemical orphysical interactions, e.g. hydrogen bonds or Ionic bonds, between thesolvent, solvents and/or additive and the crystal face may be formed.Steric effects may also have to be considered to allow thesolvent-crystal or additive-crystal interaction. E.g. in the case of anionic compound, preferably a polar solvent or additive is chosen, and incase of hydrogen-binding compounds, preferably a hydrogen bond-donor oracceptor solvent or additive is chosen.

Suitable solvents are those known to the skilled person, such as

-   -   a) a polar protic solvent such as an alkanol e.g. a C₁₋₆        alkanol, preferably a C₁₋₄ alkanol, wherein the alkyl radical        may be linear or branched such as methanol, ethanol or        isopropanol; or a cycloalkanol, e.g. cyclohexanol; water; an        organic acid e.g. a C₁₋₈ carboxylic acid, e.g. acetic acid,    -   b) a dipolar aprotic solvent such as an ester e.g. a carboxylic        acid ester e.g. isopropyl acetate, ethyl acetate; a ketone e.g.        acetone; an ether e.g. diethyl ether, methyl t-butyl ether, an        amide e.g. formamide, dimethylformamide; dimethylsulfoxide; a        nitrile e.g. acetonitrile,    -   c) a non-polar solvent such as an alkane e.g. hexane or heptane,        a cycloalkane, e.g. cyclohexane; or an aromatic hydrocarbon,        e.g. toluene or xylene; or    -   d) any mixture thereof.

Suitable additives are those known to the skilled person e.g. thosedescribed in J. Nyvit and J. Ulrich “Admixtures in Crystallization” (VCHWeinheim, 1995), the contents thereof being incorporated herein byreference. The additive may be present in an amount of about 1 ppm toabout 10% by weight of the drug substance.

The crystalline suspension is prepared by methods known to a skilledperson.

Typically, the crystals are dispersed in a solvent system so that asignificant amount of drug substance, e.g. less than 70% by weight, e.g.less than 50% by weight, e.g. about 10 to about 30% by weight of drugsubstance, dissolves upon heating and recrystallizes upon cooling.

The temperature oscillation is performed by heating and cooling thecrystalline suspension to predetermined temperature, conveniently understirring. The parameters for the temperature oscillation depend upon thenature of the solvent or solvent mixture, the nature of the crystals,the desired particle size and/or desired bulk density and may beoptimized using standard tests. The particle size of the processedcrystals may be assessed e.g. by microscopy.

The mean temperature and the temperature amplitude may be chosen tobring a significant amount of drug substance into solution, e.g. between10 and 30% of drug substance. Typically, the temperature amplitude maybe about e.g. about ±1° C. to about ±20° C., e.g. about ±5° C. to ±10°C. The temperature amplitude may be different or the same for eachoscillation, preferably it is the same for each oscillation.

The temperature oscillation curve may be in the form of approximately asinus curve with a temperature holding step or approximately a zig-zagcurve, i.e. a curve comprising a substantially linear heating step and asubstantially linear cooling step. Preferably, the temperatureoscillation curve is approximately a zig-zag curve, more preferably withthe same temperature amplitude. Typically, the oscillation starts withheating of the suspension.

In order to avoid total process time of several days, e.g. of more thantwo days, heating time and cooling time may be each e.g. about 20 toabout 120 minutes, e.g. about 80 minutes. Between heating and cooling,there may be a temperature holding step, e.g. of a duration of about 5min. Preferably, the heating time may be shorter than the cooling time,e.g. the heating time may be about 25 minutes and the cooling time maybe about 80 minutes.

In general, the higher the number of oscillations, the more the aspectratio tends towards 1:1 and the larger the particles. Practically, thenumber of oscillations may be about 6 to about 16, e.g. about 8 to about10, oscillations.

Finally, the suspension is cooled to a temperature below about 23° C. Inorder to reduce the solubility of the crystals In the solvent system.Addition of a further solvent wherein the crystals have a low solubilitymay increase the yield of the process. Finally, the crystals arefiltered and dried. Drying of the crystals, e.g. in a rotary dryer, mayfurther increase the bulk density.

Crystals of the acicular drug substance preferably have a mean aspectratio of greater than 2:1, more preferably greater than 5:1, mostpreferably greater than 10:1 before the process of the invention iscarried out. In particular, the present invention relates to aciculardrug substances such as mycophenolic acid or a mycophenolate salt inacicular form, preferably mycophenolate salt. The acicular drugsubstance may be one of the polymorphic forms of mycophenoiate sodiumdescribed below. Preferably the acicular drug substance is in the formof a crystal modification of mycophenolate sodium anydrate (modificationA), mycophenolate sodium hydrate or the hemisalt of anhydrous mycophenolate sodium as described at A, B or C below.

The mycophenolic acid or mycophenolate salt is most preferably in anamount of about 95%, preferably about 98%, even more preferably about100%, in the form of its anhydrate. Examples of mycophenolate saltsinclude e.g. cationic salts of mycophenolic acid, e.g. of alkali metals,especially the sodium salt. Preferred salt is the mono-sodium salt.

The crystals obtained by the process of the invention have an aspectratio of about 10:1 to about 1:1, e.g. about 5:1 to about 2:1, and/or abulk density of above about 200 kg/m^(3,) e.g. of between about 300 andabout 600 kg/m³, e.g. 500 kg/m³.

In accordance with the foregoing the present invention further providescrystals of mycophenolic acid or a mycophenolate salt in acicular formwith an aspect ratio of about 10:1 to 1:1 and/or a bulk density of aboveabout 200 kg/m³, e.g. prepared by the process of the invention describedherein. A preferred solvent system is a mixture of polar proticsolvents, e.g. a mixture of water and an alkanol such as indicatedabove. A typical temperature oscillation is at a mean temperature of42-47° C. with an amplitude of ±5-7° C.

In a further aspect, the present invention relates to particular crystalforms or modifications of mycophenolic acid or mycophenolate sodium,having properties as described below.

A. In one embodiment, the Invention relates to a crystal modification A(Mod A) of mycophenolate sodium anhydrate. The single crystal structureof modification A could be solved. Mod A crystallizes in the monoclinicspace group P2₁ /c. The cell dimension and volume are shown below. Inthe following dimensions are in Å, volume in Å³. space group: P2₁/c a:16.544(4) b: 4.477(1) c: 21.993(3) β: 92.14(1) V: 1627.8(6) Z: 4 cal.Density: 1.397 g/cm

Differential Scanning Calorimetry (DSC)

The DSC curve is measured in pans with a heating rate of 10K/min foridentity. The DSC curve of modification A shows an endothermic peak atabout 191 ° C. due to the melting process of the drug substance(corrected onset temperature with indium, instrument: Perkin ElmerDSC-7).

Thermogravimetry

The thermogravimetry curve of the anhydrous mycophenolate sodium Mod Ashows no significant amount of loss on mass during heating (instrument:Mettler TGA850).

X-Ray Powder Diffraction

The X-ray powder diffraction pattern of Mod A is shown in FIG. 1. Thecalculated X-ray powder pattern using the single crystal structural datais in agreement with the experimental XRPD (instrument: Scintag XDS,calculations are performed e.g. with CERIUS 2 software package (MSI)).

Morphology

Mod A crystals are acicular, columnar shaped.

Infra-red Spectrum

The following infra-red absorption bands are typical for anhydrousenolate sodium, modification A 2927, 2863 C—H aliphatic 1718 C═O lactone1616 C═C olefinic/aromatic 1572 C═O carboxylic acid 1451 CH₂, CH₃ 1372CH₃ 1267 C—O phenol  832 C—H o.o.p. trisubstituted olefin

B. In a further embodiment, the invention relates to a crystalmodification of mycophenolate sodium hydrate having properties asdescribed below.

Differential Scanning Calorimetry (DSC)

The DSC curve is measured in normal closed and tightly closed pans witha heating rate of 10K/min for identity. The DSC curve of mycophenolatesodium hydrate shows several endothermic peaks with both pan types andfinally a peak about 191 ° C. corresponding to the melting process ofmycophenolate sodium Mod A (instrument: Perkin Elmer DSC-7)

Thermogravimetry

The thermogravimetry curve of mycophenolate sodium hydrate shows a losson mass during heating up to about 150° C. of about 5%, corresponding toa monohydrate (instrument: Mettler TGA850).

X-ray powder diffraction

The X-ray powder diffraction pattern of mycophenolate sodium hydrate isshown in FIG 2. X-ray powder pattern can clearly be distinguished fromthe diffraction pattern of Mod A (instrument: Scintag XDS).

Morphology

The crystals of the hydrate are needle like, acicular shaped particleswith a length of 20 to 600 μm.

Temperature Controlled X-ray Diffraction of Hydrate Form

The crystalline hydrate is heated on the XRPD sample holder under 0%r.h. and the XRPD pattern recorded at different temperatures (shown inFIG. 3). A change of the X-ray powder pattern is obtained while heatinginto the anhydrous crystalline Mod A at 184° C. Between 30° C. and 184°C. under these conditions, two further crystalline forms which are verysimilar to the hydrate regarding the XRPD pattern are obtained. Thisresult corresponds very well to the DSC curve.

C. In a further embodiment, the invention relates to a crystalmodification of the hemisalt of mycophenolate sodium (anhydrous) havingproperties as described below.

The single crystal structure of the hemisalt of mycophenolate sodiumcould be solved. It crystallizes in the triclinic space group P-1. Thecell dimension and volume are shown below.

space group: P-1 a: 11.172(6) b: 12.020(6) c: 13.441(2) α: 73.09(7) β:71.79(6) Y: 84.63(6) V: 1641(2) Z: 2

Differential Scanning Calorimetry (DSC)

The DSC curve Is measured in pans with a heating rate of 10K/min foridentity. The DSC curve of mycophenolate sodium adduct (hemisalt) showsan endothermic peak at about 158° C. due to the melting process of thesubstance (instrument: Perkin Elmer DSC-7).

Thermogravimetry

The thermogravimetry curve of mycophenolate sodium adduct (hemisalt)shows no significant amount of loss of mass during heating up to themelting of the substance (instrument: Mettler TGA850).

X-ray powder diffraction

The X-ray powder diffraction pattern of mycophenolate sodium adduct(hemisalt) is shown in FIG. 4. The calculated X-ray powder pattern usingthe single crystal structural data is in agreement with the experimentalXRPD (instrument: Scintag XDS).

Morphology

The crystals of the hemisalt (adduct) have a acicular, columnar and lathshaped morphology with a length between 20 and 200 μm and a widthbetween 5 and 50 μm.

D. In a further embodiment, the invention relates to a crystalmodification of mycophenolate sodium methanol solvate having propertiesas described below.

The single crystal structure of the methanol solvate of mycophenolatesodium could be solved. It crystallizes in the triclinic space groupP-1. The cell dimension and volume are shown below.

Crystallographic space group: P-1, Z = 2, V = 976.3 Cell dimension: a:7.761 α: 109.96° b: 9.588 β: 95.99° c: 14.094 Y: 83.05°

Differential Scanning Calorimetry (DSC)

The DSC curve is measured In pans with a heating rate of 10K/min foridentity. The DSC curve of ERL080 methanol solvate shows an endothermicpeak at about 66° C. due to the melting process of the methanol solvatefollowed by small additional endothermic peaks up to a transformation tomycophenolate sodium, Mod A and the corresponding endothermic meltingpeak at about 188° C. (instrument: Perkin Elmer DSC-7).

Thermogravimetry

The thermogravimetry curve of the methanol solvate shows a significantamount of loss on mass during heating of about 7.4%. (instrument:Mettler TGA850)

X-Ray Powder Diffraction

The X-ray powder diffraction pattern of mycophenolate sodium methanolsolvate is shown in FIG. 5. The calculated X-ray powder pattern usingthe single crystal structural data is in agreement with the experimentalXRPD (instrument: Scintag XDS).

Morphology

The crystals of the methanol solvate are mostly plate shaped aggregatesof columnar shaped particles with a diameter between 100 and 200 μm.

E. In a further embodiment, the invention relates to a crystalmodification of mycophenolate sodium methanol solvate II havingproperties as described below.

The single crystal structure of the methanol solvate II of mycophenolatesodium could be solved. It crystallizes in the triclinic space groupP-1. The cell dimension and volume are shown below.

Crystallographic space group: P-1, Z = 2, V = 996.4 Cell dimension: a:9.179 α: 113.27° b: 10.724 β: 101.76° c: 12.098 Y: 104.44°

F. In a further embodiment, the Invention relates to a crystalmodification of mycophenolate disodium salt, monohydrate havingproperties as described below.

Differential Scanning Calorimetry (DSC)

The DSC curve is measured in pans with a heating rate of 10K/min foridentity. The DSC curve of mycophenolate disodium salt, monohydrateshows several endothermic peaks up to the melting of the substance intightly closed pans and only one endothermic peak at about 179° C. innormal closed pans (Perkin Elmer DSC-7, vsp pans).

Thermogravimetry

The thermogravimetry curve of mycophenolate disodium salt, monohydrateshows a loss on mass during heating of about 5% up to about 250° C.(instrument: Mettler TGA850).

X-ray Powder Diffraction

The X-ray powder diffraction pattern of mycophenolate disodium salt,monohydrate is shown in FIG. 6. The X-ray powder diffraction pattern ofthe disodium salt can clearly be distinguished from the X-ray powderpattern of Mod A. (instrument: Scintag XDS).

Morphology

The crystals of the disodium salt monohydrate are lath shaped, lightbreakable particles with riled surfaces.

G. In a further embodiment, the invention relates to a crystalmodification of mycophenolate disodium salt, pentahydrate havingproperties as described below.

The single crystal structure of the mycophenolate disodium salt,pentahydrate could be solved. It crystallizes in the monoclinic spacegroup. The cell dimension and volume are shown below.

Crystallographic space group: P 2₁/c, Z = 4, V = 2128 Cell dimension: a:14.495 β: 97.15° b: 17.613 c: 8.401

After storage of the di-sodium salt monophydrate for 4 weeks at 40°C./75% r.h. in open ampoules, it changes to the di-sodium salt ∥pentahydrate. This is the only material obtained beside the singlecrystals. The identification of the pentahydrate is done using thesingle crystal structural data.

Thermogravimetry

The thermogravimetry curve of di-sodium salt II pentahydrate shows asignificant amount of loss on mass during heating of about 19.8%.(instrument: Mettler TGA850)

X-Ray Powder Diffraction

The X-ray powder diffraction pattern of di-sodium salt II pentahydrateis shown in FIG. 7. The calculated X-ray powder pattern using the singlecrystal structural data is in agreement with the experimental XRPD(instrument: Scintag XDS).

H. In a further embodiment, the invention relates to a crystalmodification of mycophenolic acid having properties as described below.

The single crystal structure of mycophenolic acid (salt free form ofmycophenolate sodium) could be solved. It crystallizes in the triclinicspace group P-1. The cell dimension and volume are shown below.Crystallographic space group: P-1, Z = 2, V = 796.3 Cell dimension: a:7.342 α: 102.70° b: 9.552 β: 90.89° c: 11.643 γ: 90.74°

Differential Scanning Calorimetry (DSC)

The DSC curve is measured in pans with a heating rate of 10K/min foridentity. The DSC curve of mycophenolic acid shows an endothermic peakat about 143 ° C. due to the melting process of the substance(instrument: Perkin Elmer DSC-7).

Thermogravimetry

The thermogravimetry curve of mycophenolic acid shows no significantamount of loss on mass during heating up to the melting of the substance(instrument: Mettler TGA850).

X-Ray Powder Diffraction

The X-ray powder diffraction pattern of mycophenolic acid is shown inFIG. 8. The calculated X-ray powder pattern using the single crystalstructural data is in agreement with the experimental XRPD (instrument:Scintag XDS).

Morphology

The crystals of mycophenolic acid are irregular shaped with adhesiveparticles with a length of <50 to >400 μm.

I. In a further embodiment, the invention relates to a crystalmodification of mycophenolate sodium hydrate Form B (hydrate heated to85° C.) having properties as described below.

Form B is produced by heating the hydrate on the X-ray sample holder toabout 85° C. and then cooling the substance down to room temperature.The X-ray pattern at 85° C. and after subsequent cooling to roomtemperature (shown in FIG. 9) correspond to each other (instrument:Scintag).

Differential Scanning Calorimetry (DSC)

The DSC curve is measured in pans with a heating rate of 10K/min foridentity. The DSC curve shows three endothermic peaks. The finalendothermic peak corresponds to the melting of mod A. (instrument:Perkin Elmer DSC-7).

Thermogravimetry

The thermogravimetry curve of Form B shows a loss on mass during heatingof about 1%. (instrument: Mettler TGA850)

X-Ray Powder Diffraction

The X-ray powder diffraction pattern of Form B is shown in FIG. 10(instrument: Scintag XDS).

J. In a further embodiment, the invention relates to a crystalmodification of mycophenolate sodium hydrate Form C (hydrate heated toabout 155° C.) having properties as described below.

The Form C is produced by heating the hydrate on the X-ray sample holderto about 155° C. and then cooling the substance down to roomtemperature. The X-ray pattern at 155° C. and after subsequent coolingto temperature (shown in FIG. 11) correspond to each other (instrument:Scintag )

Differential Scanning Calorimetry (DSC)

The DSC curve is measured in pans with a heating rate of 10K/min foridentity. The DSC curve of Form C shows two endothermic peaks: meltingof Form C transition to Mod A and then melting (2^(nd) endotherm) of ModA. (instrument: Perkin Elmer DSC7).

Thermogravimetry

The thermogravimetry curve of Form C shows a loss on mass during heatingof about 0.2%. (instrument: Mettler TGA850)

X-Ray Powder Diffraction

The X-ray powder diffraction pattern of Form C is shown in FIG. 12(instrument: Scintag XDS).

In further embodiments, the invention relates to pharmaceuticalpreparations comprising one or more of the above crystal modifications,e.g. alone or in a mixture comprising two or more of the above crystalmodifications. Preferably the preparations comprise one of the crystalmodifications in greater than 90%, more preferably greater than 95%,most preferably greater than 99% polymorphic purity, e.g as asdetermined by X-ray powder diffraction, DSC and IR spectrum. Theinvention also relates to the essentially pure form of each of the abovecrystal forms.

The various crystal modifications may be prepared by crystallization orrecrystallization of any forms or mixtures of mycophenolic acid ormycophenolate sodium in a solution comprising water and/or anappropriate solvent. Modification A may be formed e.g. bycrystallization of mycophenolate sodium from isopropanol. The hydrateform may be produced by dissolving mycophenolate sodium in methanol,adding aqueous sodium hydroxide and precipitating this solution inisopropanol. Heating the hydrate form to 85 or 155° C. leads to theformation of forms B and C respectively. The hemi-salt may be obtainedby crystallization of mycophenolate sodium from water, preferably at pH4 to 6. If the pH is lowered to below 2, the free acid form may beobtained. Methanol solvate forms may be obtained by crystallization ofmycophenolate sodium from a mixture of methanol and water. Disalt formsmay be obtained by crystallization from an aqueous solution ofmycophenolate sodium, preferably containing an increased concentrationof sodium ions and at a pH greater than 8.

Crystals in the form of one of the modifications described above at A toJ, as well as crystals obtained by the modifying or recrystallisingprocesses of the present invention are referred to henceforth as“crystals of the invention”. The crystals of the invention may beformulated for administration in any convenient way, e.g. in the form oftablets.

Tablets may be obtained e.g. by granulation of the crystals of theinvention followed by compression. Tablets comprising crystals of theinvention have an improved hardness, e.g. a hardness of about 130N toabout 160N. The abrasion is less than about 0.5%, e.g. less than about0.3%. Tablets may be coated tablets, e.g. enteric coated tablets.Suitable coating material comprises, e.g. hydroxypropyl methylcellulosephthalates, e.g. HPMCP HP50, and optionally pigments, e.g. Iron oxide,Indigotine, e.g. indigotine lake, and/or titanium dioxide.

Tabletting procedures which may be used may be conventional or known inthe art or based on such procedures e.g. those described in L. Lachmanet al. The Theory and Practice of Industrial Pharmacy, 3rd Ed, 1986, H.Sucker et al, Pharmazeutische Technologie, Thieme, 1991, Hagers Handbuchder pharmazeutischen Praxis, 4th Ed. (Springer Verlag, 1971)SandRemington's Pharmaceutical Sciences, 13th Ed., (Mack Publ., Co., 1970)or later editions.

Accordingly, in another aspect, the present invention provides apharmaceutical composition, e.g. in the form of tablets, comprisingcrystals of the invention, and a pharmaceutically acceptable carrier.

In another aspect, the present invention provides drug substancecrystals of the invention for use as a pharmaceutical or in thepreparation of a pharmaceutical composition for use in any methoddescribed in the art for said drug substance. Furthermore, the presentinvention provides the use of crystals and the pharmaceuticalcompositions of the invention for the preparation of a medicament forthe treatment of any condition known therefore and described in the art.

The compositions of the invention comprising mycophenolic acid or amycophenolate salt are useful as immunosuppressants as indicated bystandard tests. The activity and characteristics of the compositions ofthe invention may be indicated in standard clinical trials or animaltest as described e.g. In WO 97/38689, the content of which isincorporated herein by reference.

The pharmaceutical compositions of the invention comprising mycophenolicacid or mycophenolate salt are useful as immunosuppressants and inparticular for the following conditions:

-   -   a) Treatment and prevention of native or transgenic organ,        tissue or cellular allograft or xenograft transplant rejection,        e.g. for the treatment of recipients of e.g. heart, lung,        combined heart-lung, liver, kidney, pancreatic, skin, pancreatic        islet cell, neural cell or comeal transplant; including        treatment and prevention of acute rejection; treatment and        prevention of hyperacute rejection, e.g. as associated with        xenograft rejection; and treatment and prevention of chronic        rejection, e.g. as associated with graft-vessel disease. The        compositions of the invention are also indicated for the        treatment and prevention of graft-versus-host disease, such as        following bone marrow transplantation.    -   b) Treatment and prevention of autoimmune disease, e.g.        immune-mediated disease and inflammatory conditions, in        particular inflammatory conditions with an etiology including an        immunological component such as arthritis (for example        rheumatoid arthritis, arthritis chronica progrediente and        arthritis deformans) and rheumatic diseases. Specific        immune-mediated disease for which the compositions of the        invention may be employed include, autoimmune hematological        disorders, including, but not limited to hemolytic anaemia,        aplastic anaemia, pure red cell anaemia and idiopathic        thrombocytopenia), systemic lupus erythematosus, polychondritis,        sclerodoma, Wegener granulosis, dermatomyositis, polymyositis,        chronic active hepatitis, primary bilary cirrhosis, myasthenia        gravis, psoriasis, Steven-Johnson syndrome, pemphigus,        idiophatic sprue, inflammatory bowel disease (including e.g.        ulcerative colitis and Crohn's disease), endocrine        ophthalmophathy, Graves disease sarcoidosis, multiple sclerosis,        juvenile diabetes (diabetes mellitus type I), non-infectious        uveltis (anterior and posterior), keratoconjunctivitis sicca and        vemal keratoconjunctivitis, interstitial lung fibrosis,        psoriatic arthritis, vasculitis, glomerulonephritides (with and        without nephrotic syndrome, e.g. including idiophatic nephrotic        syndrome or minimal change nephropathy) and juvenile        dermatomyositis.

For the above uses the required dosage will of course vary depending onthe drug substance used, the mode of administration, the particularcondition to be treated and the effect desired.

Accordingly, the present invention further provides a method fortreating and/or preventing native or transgenic organ, tissue orcellular acute or chronic allograft or xenograft transplant rejection orgraft-versus-host diseases, or treating and/or preventing an autoimmunedisease, e.g. as disclosed above, in a subject, such as a human or otheranimal subject, comprising administering to the subject an effectiveamount of a composition comprising crystals of the invention ofmycophenolic acid or a mycophenolate salt.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows the X-ray powder diffraction pattern of anhydrousmycophenolate sodium modification A.

FIG. 2 shows the X-ray powder diffraction pattern of mycophenolatesodium hydrate.

FIG. 3 shows XRPD pattern recorded at different temperatures when thecrystalline hydrate is heated on the XRPD sample holder under 0%relative humidity.

FIG. 4 shows the X-ray powder diffraction pattern of mycophenolatesodium adduct (hemisalt).

FIG. 5 shows the X-ray powder diffraction pattern of mycophenolatesodium methanol solvate.

FIG. 6 shows the X-ray powder diffraction pattern of mycophenolatedisodium salt, monohydrate.

FIG. 7 shows the X-ray powder diffraction pattern of di-sodium salt IIpentahydrate.

FIG. 8 shows the X-ray powder diffraction pattern of mycophenolic acid.

FIG. 9 shows the X-ray pattern at various temperatures of mycophenolatesodium hydrate Form B.

FIG. 10 shows the X-ray powder diffraction pattern of Form B.

FIG. 11 shows The X-ray pattern at various temperatures formycophenolate sodium hydrate Form C.

FIG. 12 shows the X-ray powder diffraction pattern of Form C.

The following Examples serve to illustrate the invention.

EXAMPLE 1

Fine long rods of mycophenolate mono-sodium salt, anyhdrate (mod. A) areobtained by crystallization from isopropanol, filtration and drying at50° C. in a paddle dryer. The crystals have a mean length of 20-50 μm, amean width of about 1 μm and a bulk density of about 180-200 kg/m³. Thecrystal habit of these crystals is modified as described in Examples 2to 6.

EXAMPLE 2 TO 5

40 g of mycophenolate mono-sodium salt crystallized as described inExample 1 are suspended in 120 g of methano/water in a mixing ratio of95/5 in a stirred vessel. The suspension is oscillated at a meantemperature of 44° C. with an amplitude of +/−6° C. The period of oneoscillation is 110 min, the number of oscillations is given in Table 1.The process temperature is controlled in a way that it performs azigzag-curve over time.

240 g of ethanol are added and the suspension is cooled to 0° C. within3 h. After filtration and drying in a rotary dryer, large compactcrystals are obtained. The final bulk density is given in Table 1. TABLE1 Ex. 2 Ex. 3 Ex. 4 Ex. 5 number of oscillations 5 6 10 16 bulk density[kg/m³] 280 310 380 490

Similarly, the mycophenolate mono-sodium salt may be suspended inmethanol/water in another mixing ratio ranging between about 98:2 and90:10.

EXAMPLE 6

20 g of mycophenolate mono-sodium salt crystallized as described inExample 1 are suspended in 60 g of methanol/water In a mixing ratio of95/5 in a stirred vessel. The suspension is oscillated at a meantemperature of 44° C. with an amplitude of +/−6° C. The period of oneoscillation is 160 min, the number of oscillations is 8. The processtemperature is controlled in a way that it performs a sinus-curve overtime.

180 g of ethanol are added during 180 min whereby the oscillation iscontinued. Then the suspension is cooled to 0° C. within 3h. After 2h,the crystals are filtred and dried in a rotary dryer. The final bulkdensity is 350 kg/m^(3.)

EXAMPLE 7

Component amount in [mg] amount in [mg] Mycophenolate sodium 192.4 384.8Anhydrous lactose 45.0 90.0 Crospovidone 32.5 65.0 Povidone K30 PH 20.040.0 Maize Starch 10.3 20.5 Colloidal silicon dioxide 6.6 13.2 Magnesiumstearate 3.3 6.5 Enteric coating: Hypromellose phthalate HP50 42.0 65.0Titanium dioxide 2.9 4.7 Iron oxide yellow 0.08 0.17 Iron oxide red —0.17 Indigo carmine 0.039 —

Mycophenolate sodium, Povidonee ® K30, silica, colloidal anhydrous aremixed, wet-granulated using ethanol 94% (w/w), mixed with lactoseanhydrous, maize starch, Crospovidone®, and magnesium stearate; andcompressed to tablets. The tablets are coated in a perforated pan coaterwith a solution of the coating ingredients In ethanol (with 5%isopropanol)/acetone. The tablets have a hardness of 130 to 156 KN.Abrasion is less than 0.3%.

1. A process for modifying the crystal habit of an acicular drugsubstance comprising suspending said crystalline drug substance in asolvent system having an effect on the crystal habit and subjecting saidsuspension to a temperature oscillation.
 2. A process forrecrystallising an acicular drug substance comprising suspending saidcrystals in a solvent system having an effect on the crystal habit andsubjecting said suspension to a temperature oscillation.
 3. A processaccording to claim 1 wherein the crystal habit is modified in that themean aspect ratio of the processed crystals is smaller than about 10:1.4. A process according to claim 1 wherein the drug substance aftertemperature oscillation has a bulk density of about above 200 kg/m^(3.)5. A process according to claim 1 wherein the temperature oscillation isin form of a zig-zag curve.
 6. A process according to any one of claim 1wherein the crystals produced have a mean aspect ratio of the processedcrystals smaller than about 10:1 or a bulk density of about 200 kg/m³.7. Crystals of an acicular drug substance with an aspect ratio of about10:1 to 1:1 and/or a bulk density of above about 200 kg/m^(3.) 8.Crystals according to claim 7 wherein the acicular drug substance ismycophenolic acid, or a mycophenolate salt.
 9. A pharmaceuticalcomposition in the form of tablets, comprising crystals of claim 7 inassociation with a pharmaceutically acceptable carrier.
 10. Crystals ofclaim 8 for use as a pharmaceutical.
 11. A crystal modification ofmycophenolic acid or mycophenolate sodium having one of the followingcharacteristic crystal structures, determined by means of an X-raysingle crystal analysis, or having an X-ray powder diffraction patternas defined below: a) mycophenolate sodium anhydrate, modification A;crystal system: monoclinic space group: P2₁/c a: 16.544(4) b: 4.477(1)c: 21.993(3) β: 92.14(1)° V: 1627.8(6) Z: 4 cal. Density: 1.397 g/cm

b) mycophenolate sodium hydrate; having an X-ray powder diffractionpattern with characteristic signals substantially the same as thoseshown in FIG. 2; c) hemisalt of mycophenolate sodium anhydrate; crystalsystem: triclinic space group: P-1 a: 11.172(6) b: 12.020(6) c:13.441(2) α: 73.09(7)° β: 71.79(6)° Y: 84.63(6)° V: 1641(2) Z: 2

d) mycophenolate sodium methanol solvate; crystal system: triclinicspace group: P-1 a: 7.761 b: 9.588 c: 14.094 α: 109.96° β: 95.99° Y:83.05° V: 976.3 Z: 2

e) mycophenolate sodium methanol solvate II; crystal system: triclinicspace group: P-1 a: 9.179 b: 10.724 c: 12.098 α: 113.27° β: 101.76° Y:104.44° V: 996.4 Z: 2

f) mycophenolate disodium salt, monohydrate; having an X-ray powderdiffraction pattern with characteristic signals substantially the sameas those shown in FIG. 6; g) mycophenolate disodium salt, pentahydrate;crystal system: monocimic space group: P 2₁/c, a: 14.495 b: 17.613 c:8.401 β: 97.15° V: 2128 Z: 4

h) mycophenolic acid; crystal system: triclinic space group: P-1 a:7.342 b: 9.552 c: 11.643 α: 102.70° β: 90.89° Y: 90.74° V: 796.3 Z: 2

i) mycophenolate sodium hydrate form B; having an X-ray powderdiffraction pattern with characteristic signals substantially the sameas those shown in FIG. 10; j) mycophenolate sodium hydrate form C;having an X-ray powder diffraction pattern with characteristic signalssubstantially the same as those shown in FIG. 12;
 12. A processaccording to claim 2 wherein the crystal habit is modified in that themean aspect ratio of the processed crystals is smaller than about 10:1.13. A process according to claim 2 wherein the drug substance aftertemperature oscillation has a bulk density of about above 200 kg/m³. 14.A process according to claim 2 wherein the temperature oscillation is inform of a zig-zag curve.
 15. A process according to claim 2 wherein thecrystals produced have a mean aspect ratio of the processed crystalssmaller than about 10:1 or a bulk density of about 200 kg/m³.
 16. Apharmaceutical composition in the form of tablets, comprising crystalsof claim 2 in association with a pharmaceutically acceptable carrier.